European Journal of Pediatrics https://doi.org/10.1007/s00431-020-03744-y ORIGINAL ARTICLE Early surfactant replacement guided by lung ultrasound in preterm newborns with RDS: the ULTRASURF randomised controlled trial Javier Rodriguez-Fanjul 1 & I. Jordan 2,3 & M. Balaguer 2 & A. Batista-Muñoz 4 & M. Ramon 4 & S. Bobillo-Perez 2,5 Received: 1 April 2020 / Revised: 13 July 2020 / Accepted: 16 July 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020 Abstract This study aimed to investigate whether using lung ultrasound (LUS) scores in premature newborns with respiratory distress syndrome (RDS) allows for earlier surfactant therapy (within the first 3 h of life) than using FiO2 criteria. This was a randomised, non-blinded clinical trial conducted in a neonatal intensive care unit. The inclusion criteria were newborns with a gestational age of ≤ 32 weeks and RDS. Patients meeting the inclusion criteria were randomly assigned to two groups: the ultrasound group, administered surfactant based on LUS score and/or FiO2 threshold, and the control group, guided by FiO2 only. Fifty-six patients were included. The ultrasound group received surfactant earlier (1 h of life vs. 6 h, p < 0.001), with lower FiO2 (25% vs. 30%, p = 0.016) and lower CO2 (48 vs. 54, p = 0.011). After surfactant treatment, newborns in the ultrasound group presented a greater SpO2 (p = 0.001) and SpO2/FiO2 ratio (p = 0.012). Conclusions: LUS score allowed an earlier surfactant therapy, reduced oxygen exposure early in life and a better oxygenation after the treatment. This early surfactant replacement may lead to reduced oxygen exposure. What is Known: • Lung ultrasound scores predict the need for surfactant therapy in premature newborns. What is New: • This study shows that using lung ultrasound scores improves the timeliness of surfactant replacement compared with using FiO2 alone. Keywords Lung ultrasound . Respiratory distress syndrome . Premature newborns . Surfactant Abbreviations LUS Lung ultrasound CXR Chest X-ray NA Neonatologist-assistant GA Gestational age nCPAP Nasal continuous positive airway pressure Communicated by Daniele De Luca * Javier Rodriguez-Fanjul 1 Neonatal Intensive Care Unit, Paediatrics Department, Hospital javier.rodriguez.fanjul@gmail.com Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain I. Jordan 2 ijordan@sjdhospitalbarcelona.org Paediatric Intensive Care Unit, Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain M. Balaguer 3 mbalaguer@sjdhospitalbarcelona.org Paediatric Infectious Diseases Research Group, Institut de Recerca Hospital Sant Joan de Déu, CIBERESP, Barcelona, Spain A. Batista-Muñoz albertbatis.hj23.ics@gencat.cat 4 Neonatal Intensive Care Unit, Paediatrics Department, Hospital Joan M. Ramon XXIII, Tarragona, Spain mramonjimenez.hj23.ics@gencat.cat 5 Disorders of Immunity and Respiration of the Paediatric Critical S. Bobillo-Perez Patient Research Group, Institut de Recerca Hospital Sant Joan de sbobillo@fsjd.org Déu, Universitat de Barcelona, Barcelona, Spain Eur J Pediatr NICU Neonatal intensive care unit This study aims to investigate if using LUS score ensures NR Neonatologist-researcher timely surfactant administration in premature patients better RDS Respiratory distress syndrome than FiO2 does. Materials and methods Introduction Design The management of respiratory distress syndrome (RDS) in This was a randomised, non-blinded clinical trial conducted in premature newborns is centred on the use of nasal continuous the NICU of Hospital Joan XXIII, Tarragona, in Spain, be- positive airway pressure (nCPAP) [1]. Determining the need tween January 2019 and March 2020. The study was carried for surfactant treatment is currently guided only by the new- out in accordance with the Declaration of Helsinki and was born’s requirement for oxygen therapy. In recent guidelines, approved by the local ethics committee and institutional re- early therapy with surfactant is suggested in patients requiring view board (EIM 136/2019). The study was registered at nCPAP of at least 6 cmH 20 and an FiO 2 over 0.3 [2]. ClinicalTrials.gov, with identifier NCT04330443. Written Certainly, this cut-off can be considered arbitrary, given that informed consent was obtained prenatally from the patients’ the current evidence is based on observational studies that parents or guardians. considered FiO2 requirements greater than 0.3 as a predictor of respiratory failure [3] and may not accurately reflect the patient’s oxygenation [4]. Therefore, it is challenging for neo- Patients natologists to identify the newborns who will benefit from early surfactant treatment (within the first 3 h of life), which Inclusion criteria were premature newborns under the gesta- is known to decrease pneumothorax and bronchopulmonary tional age (GA) of 32 weeks with RDS [18], defined as respi- dysplasia and to improve survival rates [3]. However, patients ratory distress appearing within the first 24 h of life which receiving surfactant may present side effects including brady- required nCPAP to keep peripheral oxygen saturation cardia, oxygen desaturation and pulmonary haemorrhage, (SpO2) above 90%, with clinical signs of respiratory difficulty among others [5]. (polypnoea, chest retractions, nasal flutter, etc.) and a com- For decades, clinicians have used chest X-rays (CXR) to plete, sustained and prompt response to surfactant and/or lung identify RDS, as they show the pathology’s characteristic dif- recruitment. An additional, non-mandatory criterion was lung fuse reticulogranular pattern or ground glass appearance. images that support the diagnosis. However, this technique has low sensitivity and specificity Exclusion criteria were as follows: non-acceptance of the [6]. Moreover, thanks to improvements in standard prenatal informed consent, chromosomal abnormalities, complex con- and postnatal care, the RDS-like CXR image has also become genital malformations, signs of early-onset septic shock, me- more uncommon [7]. chanical ventilation and patients who received surfactant in Lung ultrasound (LUS) has emerged as a bedside tech- the delivery room as part of advanced resuscitation following nique that helps clinicians to identify RDS patients in neonatal the pertinent European guidelines [2]. intensive care units (NICUs) [8–12]. Some studies have shown a high correlation between LUS findings and oxygen- Objectives ation status/need for surfactant therapy [13, 14]. Furthermore, some studies have shown LUS score to be a more accurate The main objective of the study was to determine if a diagno- diagnostic criterion than FiO2 [10, 13–15], and the latest sis of RDS guided by a LUS algorithm allowed for earlier European respiratory distress guidelines highlight its potential surfactant therapy (within the first 3 h of life) in comparison use in identifying patients with RDS [2]. A recent high-quality with using an FiO2 threshold alone. prospective study showed that LUS improved timeliness in The secondary objective was to assess the different surfactant administration in a tertiary NICU during two time levels of oxygen exposure in early life for each group. periods [16], but no clinical trial has evaluated the use of Other secondary outcomes were SpO2/FiO2 ratio (S/F ra- surfactant therapy guided by LUS only versus conventional tio) after surfactant therapy (see below), the need for me- FiO2 guidance. chanical ventilation (MV) (defined as MV during the first 3 Moreover, there is an increased understanding about the days of life [18]), duration of invasive and non-invasive potential lifelong impact of excessive oxygen exposure during mechanical ventilation, ventilator-free days [19], duration the first hours of life in preterm infants, and LUS may help to of supplemental oxygen requirements, length of stay in the avoid this oxygen toxicity [17] by reducing exposure to it. NICU and bronchopulmonary dysplasia [20]. Eur J Pediatr Methodology patients with a GA of < 286/7 weeks or 40% in patients whose GA was > 290/7 weeks (Fig. 1). Patients who met the inclusion criteria were randomly assigned to two groups, using the “random” function in the MS-Excel® programme. A binary sequence of random num- General patient management bers was generated following a balanced block sampling (Friedman procedure) and held by the principal investigator. Our unit follows the European guidelines for respiratory sup- A total of 6 physicians enrolled participants, all them fully port in premature newborns [2]. In the delivery room, patients trained in the use of LUS. The principal investigator assigned received face mask ventilation with continuous positive air- participants to interventions based on the randomised list. way pressure and a target peak inspiratory pressure. Patients with a gestational age of under 32 weeks were includ- Unresponsive patients were intubated in the delivery room ed as they were born during the study period: and received early surfactant administration, so they were ex- cluded from the study. Those who were responsive at birth – Ultrasound group: The neonatologist-researcher (NR) who were transferred to the NICU on nCPAP if they were born was not the attending clinician performed the LUS at ad- before 32 weeks of GA. mission during the first hour of life. The neonatologist- Once admitted to the unit, patients were placed under var- assistant (NA) for the baby was not blinded to the result iable flow nCPAP using the appropriate nasal prongs or facial of the LUS. Patients received surfactant therapy as soon as mask with a pressure between 5 and 7 cmH20, with oxygen the LUS score was higher than 8 or FiO2 requirements being increased as needed to keep SpO2 between 90 and 95%. exceeded 30% in patients with a GA of < 286/7 weeks or Patients were intubated if FiO2 > 50% despite surfactant 40% in patients whose GA was > 290/7 weeks (Fig. 1) [22]. therapy, if they had multiple episodes of apnoea (> 4 episodes This LUS threshold has been found to be the one with the per hour or > 1 episode requiring rescue with positive-pressure best diagnostic accuracy [10, 13, 14]. ventilation) or if respiratory acidosis was detected (pCO2 > – Control group: The NR performed the LUS at admission 65 mmHg and pH < 7.20 in capillary samples). during the first hour of life. The NA was not blinded to The LUS study protocol included longitudinal scans of the the result of the LUS. The patient received surfactant anterior, lateral and posterior chest walls performed with a therapy only when FiO2 requirements exceeded 30% in lineal 12 MHz probe (Sonosite Edge II) during the first hour Fig. 1. Study protocol algorithm. RDS, respiratory distress syndrome; GA, gestational age Eur J Pediatr of life once patients were in the NICU. Focus was placed on during the study. Descriptive population data are included in the pleural line, and no harmonics were used. Three scans Table 1. There were no differences between both groups as far were performed per hemithorax (anterior, lateral and posteri- as the main clinical characteristics, including gender, weight, or) and a 0- to 3-point score was given for each scanned area GA and Apgar score. Figure 3 shows the LUS images of a (with a total score ranging from 0 to 18), in accordance with patient who received surfactant and another who did not. previous studies published in the literature [11, 13, 14]; 8 was Surfactant therapy was required in 41.3% of patients in the the cut-off score for initiating surfactant treatment [16]. ultrasound group and in 62.9% of patients in the control group Clinical patient data were recorded, including SpO2 and S/F (p = 0.106). Surfactant administration occurred earlier in the ratio [21] at the time of the LUS scan and when the patient ultrasound group than in the control group, with statistically received surfactant therapy, 5 min after the procedure. CO2 significant differences: 1 h of life (IQR 1–2) vs. 6 h (IQR 4– and pH were analysed before surfactant administration, using 6.5), with p < 0.001. Figure 4 represents the proportion of arterialised capillary blood samples. We acknowledge that S/F patients who received early surfactant therapy (in the first is an imperfect oxygenation metric, as it may be influenced by 3 h of life) in each group. All patients in the ultrasound group foetal haemoglobin, peripheral perfusion, patent ductus received surfactant therapy based on the LUS score threshold. arteriosus, temperature and other factors. Surfactant therapy Table 2 summarises the results of the secondary outcomes. was exclusively administered through less invasive surfactant Patients in the ultrasound group had better oxygenation after administration (LISA). The first dose given was 200 mg/kg of surfactant therapy, with lower FiO2 requirements and a better poractant alfa (Curosurf ®, Chiesi Farmaceutici, Parma, Italy) S/F. However, no differences were detected regarding respi- [22]. Bradycardia was defined as a heart rate of less than ratory support (days of non-invasive and invasive mechanical 80 bpm and desaturation was defined as a drop in oxygen ventilation, ventilator-free days and duration of oxygen ther- saturation to < 85%. These complications were considered to apy) or frequency of bronchopulmonary dysplasia. be related to the procedure if they were recorded during the next The frequency of complications after surfactant administra- 30 min after the surfactant therapy. Ventilator-free days were tion was no different between groups: desaturation occurred in calculated as the number of days in the NICU without invasive 4 (30.8%) patients in the ultrasound group and in 6 (37.5%) in mechanical ventilation, within the first 28 days of life; this the control group, bradycardia in 1 (7.7%) patient in the ultra- number is zero for patients who died in the NICU [19]. sound group and in 2 (12.5%) in the control group and apnoea The sample size was calculated using the ene3.0® pro- in 1 (6.3%) newborn in the control group (all p = 1.000). The gramme. A sample size of 40 patients for each group was median duration of the LUS scan was 2 min (IQR 2–3). required if assuming 80% power to reject the null hypothesis (no differences between the lung ultrasound and control groups) and accepting an alternative hypothesis with a two- Discussion tailed type I error (alpha) value as determined by the bibliogra- phy. We performed a pre-analysis to detect differences between This study demonstrates that the use of LUS improves the data from previous studies [16] and our data, observing a rela- timeliness of surfactant administration without increasing the tively delayed surfactant administration in our control group number of patients requiring surfactant treatment. To our (timely administration in 6% vs. 71% of cases reported by the knowledge, this is the first study to assess LUS score thresh- ESTHER study [16]). This exploratory analysis included the 56 olds vs. FiO2 requirement thresholds only to guide surfactant patients in our study, 27 and 29 patients in each respective replacement therapy in a clinical trial. group, giving us a statistically significant sample size. Moreover, patients receiving surfactant in the ultrasound The statistical analyses were performed using the SPSS® group had lower FiO2 requirements, better oxygenation (S/F 26.0. Categorical variables were expressed as frequency ratio) and better blood gases when surfactant was adminis- (percentage) and compared using the chi-squared test or tered. No patient in the ultrasound group received surfactant Fisher’s exact test, as needed. Continuous variables were as determined by the FiO2 requirement thresholds. expressed as median (interquartile range) and compared using LUS is a simple bedside tool that is easy to perform and is the Mann-Whitney U test. A value of p < 0.05 was considered quick (our results show that the procedure lasts 2 min), has a statistically significant. high interobserver agreement among clinicians [23] irrespec- tive of observer expertise and can be repeated several times. On an LUS, patients with RDS show an irregular, thickened Results pleural line, an absence of A lines and coalescent B lines showing [24] white lung. This pattern’s severity is scored A total of 56 newborns were included, 29 in the ultrasound according to the areas involved [24–26]. Moreover, different group and 27 in the control group. Figure 2 shows the flow studies in premature newborns have shown its correlation with chart for patients. No patient was lost due to death or dropout oxygenation [13, 14] and with the quality of the endogenous Eur J Pediatr Fig. 2 Flow chart of patients surfactant available [27]. In addition, LUS score has been improvement in early surfactant administration without en- validated as being on par with other imaging techniques such countering problems when patients were treated according to as CT scans in adults [28]. LUS instead of FiO2. This data is confirmed by our results: Our findings are consistent with previous studies published patients in the ultrasound group were in better oxygenation on this matter. In their study, Raschetti et al. [16] found an conditions after surfactant treatment, receiving lower oxygen Table 1 Comparison of both groups regarding clinical data Ultrasound group (n = 29) Control group (n = 27) p prior to surfactant therapy, including oxygenation parameters Male 16 (55.2%) 15 (55.6%) 0.977 Weight (g) 1500 (1058–1808) 1520 (1245–1795) 0.909 GA (weeks) 301 (284–313) 302 (282–314) 0.669 Intrauterine growth restriction 3 (10.3%) 3 (11.1%) 1.000 Prenatal steroids (complete dose) 27 (93.1%) 24 (88.9%) 0.664 Caesarean section 13 (44.8%) 12 (44.4%) 1.000 APGAR-5 score (points) 9 (8–10) 9 (8–10) 0.609 Paw before surfactant (cmH2O) 6 (6–6) 6 (6–6) 0.270 CO2 before surfactant (mmHg) 48 (46–51.5) 54 (49–58) 0.011 pH before surfactant 7.29 (7.27–7.3) 7.26 (7.25–7.29) 0.056 Maximum FiO2 in the first hour of life (%) 25 (22.5–25) 30 (25–35) 0.016 SpO2 in the first hour of life (%) 94 (92.5–95) 93 (90–96) 0.572 S/F before surfactant 380 (372–411.5) 340 (300–423) 0.108 Data are expressed as mean (standard deviation) or median (25th –75th percentile) and number (%) as appropriate. GA gestational age, Paw mean airway pressure, S/F SpO2/FiO2 ratio. CO2 and pH were analysed using arterialised capillary blood samples Eur J Pediatr Fig. 3 a Lung ultrasound of a newborn with an LUS score < 8. b Lung ultrasound of a newborn with an LUS score > 8 therapy (25% vs. 30%) and having a better S/F ratio. CO2 was control group in comparison with other studies [16] may be higher in the control group, indicating a more severe RDS and due to our CXR procedure: in most cases, the surfactant treat- that surfactant replacement should have been administered ment was not initiated until the CXR was taken and evaluated. earlier in this group. The diffusion of CO2 is 25 times higher Therefore, we believe that LUS can be extremely useful for all than O2 diffusion in restrictive disorders, so this is consistent NICUs that tend to have a delayed CXR time. with the higher FiO2 requirements observed in the control It is well known that oxygen treatment in premature new- group. The lower S/F ratio observed after surfactant therapy borns leads to oxidative stress, damaging proteins, lipids and in both groups could be related to the number of patients who DNA and placing these fragile preterm patients at high risk for presented desaturation after the procedure, since oxygenation epigenetic changes to the DNA [18, 29]. As there is not yet a was measured very close to the surfactant administration and well-established oxygen saturation target and the cut-off value no serial evaluation was performed. Despite the better oxy- for surfactant treatment may be arbitrary, these patients may genation parameters, we did not find any improvement in receive higher oxygen content. This can trigger the activation respiratory support, such as later events (sepsis, of pro-inflammatory and pro-apoptotic pathways, which may extrapulmonary disorders). This may be explained by the contribute to bronchopulmonary dysplasia and other patholo- small sample size of our study and by several other variables gies [30] before surfactant treatment is given during the first that may affect the need for respiratory support. Moreover, it hours of life. By contrast, basing the surfactant treatment on was found that patients in the ultrasound group received sur- LUS score seems to decrease the maximal FiO2 and the dura- factant earlier and the maximal FiO2 requirement reached was tion of oxygen treatment and may help to decrease oxygen lower (28% vs. 35%), without encountering any differences in toxicity. the overall need for surfactant. The use of LUS score in the Multiple studies have evaluated the use of LUS to predict the ultrasound group resulted in earlier surfactant administration. need for surfactant or non-invasive ventilation failure in patients The timeliest surfactant administration may be achieved by with RDS [10–12]. Moreover, LUS seems to predict the need using LUS, not just using FiO2 by itself as has been done up for surfactant administration better than FiO2. Also, LUS may to now. The low rate of timely surfactant administration in the help to identify those patients who do not require surfactant Fig. 4 Pie graph representing the proportion of patients who received early surfactant therapy (within the first 3 h of life) in each group Eur J Pediatr Table 2 Summary of the secondary outcomes, including Ultrasound group Control group p the respiratory requirements and (n = 29) (n = 27) oxygen exposure in early life FiO2 after surfactant (%) 28 (25–30) 35 (31–40) < 0.001 SpO2 after surfactant (%) 93.5 (92–95) 90 (90-90.8) 0.001 S/F after surfactant 345 (290–381) 285 (241–300) 0.012 MV 5 (17.2%) 10 (37.0%) 0.095 Duration of MV (days) 2 (1–4.5) 2 (1.8–4.3) 0.523 Ventilator-free days 28 (28–28) 28 (26–28) 0.082 NIV 29 (100%) 27 (100%) 1.000 Duration of NIV (days) 3 (2–17) 4 (3–22) 0.428 Duration of oxygen (days) 6 (2–23.5) 5.5 (3–22.8) 0.926 Length of stay in the NICU (days) 47 (34–69) 52 (38–68) 0.780 BPD 3 (10.3%) 3 (11.1%) 1.000 Data are expressed as mean (standard deviation) or median (25th –75th percentile) and number (%) as appropriate. BPD bronchopulmonary dysplasia, MV invasive mechanical ventilation, NICU neonatal intensive care unit, NIV non-invasive mechanical ventilation, and S/F SpO2/FiO2 ratio treatment and may help clinicians to identify other causes, apart Therefore, it has been shown that LUS improves timeliness from RDS, of hypoxia and non-invasive ventilation failure, so in surfactant replacement. Larger, randomised multicentre they can treat the patient accordingly [23, 31, 32]. studies are likely necessary to evaluate its use more in depth, Due to our study protocol, patients intubated in the de- especially in very premature patients under 28 weeks. Our livery room or transferred from other centres were exclud- results may help to continue the investigation into the use of ed; this may explain the early surfactant administration in LUS to guide surfactant therapy in conjunction with FiO2 both groups (median 1 h vs. 6 h) when compared with parameters. other studies [11, 14]. Our study has several limitations. Firstly, it was carried out Acknowledgements We would like to thank the premature newborns and families who accepted joining this study. at a single centre and our sample size is small. In addition, not all the patients received surfactant treatment. However, differ- Authors’ contributions JRF, SBP, ABM and MR conceived and de- ences in the need for surfactant administration between both signed the study. MB, IJ and SBP analysed the data. JRF, SBP, MB groups were not statistically significant, and earlier treatment and IJ wrote the first draft of the manuscript. ABM and MR contributed was demonstrated in the ultrasound group. Another limitation to the writing of the manuscript. All authors agree with the manuscript’s results and conclusions, jointly developed the structure and arguments for is that although we included premature newborns younger the paper, made critical revisions and reviewed and approved the final than 32 weeks, including extremely premature ones (GA < version of the manuscript. 28 weeks), it would have been better to classify the patients according to their GA, but this would have required a larger, Funding information There is no external funding source. randomised multicentre study. Another limitation was that the attending clinicians were not blinded to the ultrasound find- Compliance with ethical standards ings. However, we enrolled a homogeneous population of preterm newborns with a GA between 24 and 32 weeks with Conflict of interest The authors declare that they have no conflicts of RDS who were all treated according to the same NICU pro- interest or financial relationship with any organization. tocol, with LUS performed at a specific time in the first hour, Ethical approval This study was approved by the local Healthcare thus decreasing the possible variances in the LUS score. In Ethics Committee and the institutional review board. addition, we did not find any differences in the overall need for surfactant in both groups, which rules out the possibility of Informed consent Written informed consent was obtained from all the surfactant being given to patients who did not require it. Since parents of the participants. 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